Imino-di-fatty acid amide



Patented Nov. 26, 1946 IMINO-DI-FATTY ACID AMIDE Henry Martin and Hans Gysin, Basel, Switzerland, assignors to the firm J. R. Geigy A. G.,

Basel, Switzerland No Drawing.

' 9 Claims. 1

Heterocyclic and aromatic carboxylic acid amides have already been -described as being agents, acting in a promoting manner, while corresponding compounds of the aliphatic series often show an opposite eflicacy. Thus for example the isovalerianic acid diethyl amide (of. Deutsche med. Wochenschrift 1901, No. 49) as well as the methyl ethyl acetic acid diethyl amide (cf. Archiv der Pharmazie 1935, 202) pro-- vokes a sedativeaction.

It has now surprisingly been found that N- substituted imino-di-fatty acid amide containing at least a double substituted amide group possess valuable therapeutical properties. Such compounds may be prepared according to various methods, thus for instance in dependence of the order of succession of the substitution of the imino-N-atom and of the amination.

For instance the said compounds may readily be prepared by interaction of N-monosubstituted or N-unsubstituted e-amino fatty acid amides, whose acid amide groups are twice substituted, with halogen fatty acid derivatives. The N-un substituted or N-monosubstituted u-amino fatty acid amides required for the interaction and whose acid'amide groups are twice substituted may be produced by causing a-halogen carboxylic acid amides to react with ammonia or primary amines like methyl amine, ethyl amine, propyl amine, butyl amine, amyl amine, hexyl amine, allyl amine, isopropyl amine, cyclohexyl amine, benzyl amine, phenyl ethyl amine, phenyl isopropyl amine and so on. The u-halogen carboxylic acid amides are prepared according to known methods from the corresponding acids or functional derivatives thereof with secondary amines such as dimethyl amine, diethyl amine, diallyl amine, methyl ethyl amine, methyl propyl amine, methyl aniline, methyl benzyl amine etc. As examples of a-amino fatty acid amides which may be used, there may be enumerated:

a-methyl amino aceticacid diethyl amide, m-methyl amino aceticgacid dimethyl amide, e-methyl amino propionic acid dimethyl amide, u-methyl amino propionic acid diethyl amide, a-ethyl amino propionic acid piperidide, u-butyl amino propionic acid dimethyl amide, m-methyl amino butyric acid dimethyl amide, a-ethyl amino butyric acid diethyl amide, a-ethyl amino butyric acid morpholide, a-methyl amino valerianic acid dimethyl amide, a-methyl amino valerianic acid diethyl amide, e-methyl amino capronic acid dimethyl amide,

etc.

For the interaction of these m-amino fatty acid amides with halogen fatty acid derivatives c-, but also other halogen fatty acid derivatives are especially suitable. In this connection, there may be mentioned for. example:

Ap lication April 28, 1944, Serial 11 Switzerland May 13, 1943 chloracetic acid, chloracetic ester,

, chloracetonitrile,

chloracetic acid diethyl amide,

chloracetic acid diallylamide, a-bromopropionic acid piperidide, a-bromopropionic acid ethyl ester, a-bIOmODIODiOIIIC acid diethyl amide, a-bromopropionic acid methyl ethyl amide, a-bromopropionic acid methyl anilide, a-bromopropionic acid monoethyl amide,

a-bromobutyric acid ethyl ester,

Moreover, it is also possible to subsequently substitute, for instance to alkylate or to cycloalkylate N-substituted imino-di-fatty acid amides, whose amide groups still possess a replaceable hydrogen atom (see Titherley, J. Chem. Soc. London 79,391, (1901). Furthermore, as far as a hydrogen atom is still present in the imino group of the imino-di-fatty acid amide, the said hydrogen atom can subsequently be replaced, for instance by means of alkylating or aralkylating agents like for example dimethyl sulfate, diethyl sulfate, benzyl chloride, phenyl ethyl bromide or by any other substitution agents like methyl iodide or, e. g., by a treatment with formaldehyde and formic acid.

Finally a further preparation method of the claimed compounds consists in aminating iminodi-fatty acids with one or two free carboxylic groups or their functional derivatives, for example by interaction with secondary amines; likewise the salts of the imino-di-fatty acids or of mcnobasic derivatives may be caused to react with carbamic acid halides deriving from secondary amines.

The new compounds are partly water-soluble;

by acids they may be transformed into neutral salts. These substances may be used as thereapeutics and especially as analeptics; many of 37.2 parts of 'a-ethyl amino butyric acid diethyl amide (prepared from a-bromobutyric acid diethyl amide and ethyl amine) are dissolved in 200 parts of anisol and heated to boiling. Then under stirring 15 parts of chloracetic acid diethyl yields, by means of acids, neutral salts. The same compound is also obtained by interaction of ethyl amino acetic acid diethyl amide with a-halogenbutyric acid diethyl amides.

amide are caused to drop thereinto and the whole Very similar products are obtained by startis boiled overnight under reflux. After cooling ing from a-benzyl amino butyric acid diethyl the a-ethyl amino butyric acid diethyl amide amide or ethyl amino isobutyric acid diethyl hydrochloride separates out; the anisol solution amide. is separated from the hydrochloride, made acid The following Table 1 contains further comto Congo red by means of hydrochloric acid and pounds of the general formula freed from the organic solvent. Then the hydro- R chloric acid solution is saturated with potassium hydroxide and the N-ethyl imlno butyric acid acetic acid bis-diethyl amide is dissolved in xyl- RFN B2 ene. After distillation of the solvent the prod-- not is rectified in high vacuo. Its boiling point at 0.3 mm. pressure is 152-153 C. The product which compounds can be prepared according to is miscible with water and organic Solvents and the above mentioned two methods.

Table 1 N0. R|=R| Ro R B. P., mm. Form I Y 1 -CH1 -CHCHCH:CH3 CH;GHzCH.CON(CH3)1 143-14sc.,0.1- Liquid;

7 I 2 do. 411110113 CHCICH2CH.CON(C2H5)1 1a2-1a5c.,0.12. Do.

.--do -cH,-cH=cH, do 142-144 0., 0.02.-.. Do.

.l 4 -C,HS CHqCH1CH1CHz CHsCH.CON(C7H5)z 15a-154 0., 0.04", Do.

5 --d0 -CHzCHzCH3 CHaCHzHXlONUJzHs): 143145C.,0.05. D0.

0 .-do -CH1CH3 -cH,.c0N(c,H), 152-153 0., 0.3.-... Do.

I 7 do -CHgCH=CH1 cmomcilcomcmm 142=-144 0., (0.09).- Do.

I 8-- do -cH,cH,cH,cH: cmcmoircomcmm 1 s-151G.,0.12.... Do.

I 9 -do CHzCH CH3CH2CHgCH.CON(C2H5)z 157-160C.,0.2. Do.

CH] 1o do .do (an-(211.0orucznmn 1as-1as o..o.o4-.-. Do.

CH3 I 11 do do cm'cmcmomcrrcomega, 156159C.,0.06..-. Do.

- I 12--....-...-.do -do cmcmcncomomn -147c.,0.2...-. p0.

- I 13 .410 --do cmcmcmcrrcomcm l35-136C.,0.02--.. Do,

i4 do CHzCHzCHzCH cnscmcncomomn 14s-1510.,0.08. D0.

v p I 1 l5 .410 CHCH; cnacmcmomcncomcnm 1a7-19o0.,1.1 Do.

I 16 dO CH:4CHaCH:CHz CH3CHzCH:CHzCH.CON(CHa)z 147-150 C.,0.04- D0.

! ull-0H, l7 do CH;OH3 cmcmcrrcoN 0H, 161-164 0., 0.03---. Do.

GHQ-C CH: l I m do .....do CH3CH1CH.CON 1a9-142 Co.,0.02 Do.

1 v 19 do -0H2oH2- omortcomcmm 21s-221 0., 0.01--. Viscous.

GHQ-CH5 2o do -OH cm man l6817l0.,0.02---- Liquid.

GET-CH; I 21.-.-.-.- do -C1H5 CH3CH2CH.CONHC2HE 153 0., 0.08 Viscous.

/CH2"'CH .-..-d0 -cg 0H,; CH.CON(C:H;)= -171c.,o.2.-. D0.

GET-CH2 23 an -c.m CH .CONHCzHr 154156C.,0.15-. Liquid.

Emma: 2

43.2 parts of a-ethyl amino propionic acid dimethyl amide (prepared from a-bromopropionic acid dlmethyl amide and ethyl amine) are dis- 6 ethyl dlmethyl amide boils at 143-145 C. at a pressure of 0.25 mm. It is an almost colorless oil which is easily soluble in water and organic s01- vents and which gives neutral salts with acids.

The following Table 2 contains'turther comsolved in 150 parts of anisol, then at 150 C. 31.2 5 parts of a-bromoproplonic acid diethyl amide in pounds of the general m parts of anisol are caused to drop thereinto and the mixture is boiled under reflux during 12 c cmcon hours. The working up and purification is car- 10 R R, ried out in the manner described in Example 1. h The resulting N-ethyl-imino-dipropionic acid di- Table 2 No. Rl-Rl Re R B. P., mm. Form r I 1 CH; -cmcm omcmcomcng, -132C., Liquid. 2 do -cH cH=0H,.- o 1as-1as 0.,o.a.- [D0, 3 do -cmcmcm"; do -1s70.,0.2.---. Do.

4 -c,H, .-do n l39-140 0., o.a Do.

a --.do an cmdmcomcim 142-14 4c.,o.2.. Do.

a -CH: -0H,cmcH,cH=. Q cmc zmcomomn 132?135 0., 0.09..-- Do.

01H; 7 do -c n 168-171 0., 0.85 D0.

7 CH3 I s --do -CHzOHzCH1CH: cmcncommm), 133-136 0., 0.09;--- Do.

I o -c,m..--.. CH: cmcmcomcnm- 133 0, 1 Do. 10 do -cH,cm do 130-131 0., 0201.-.. Do.

CH: i1..--. --....do 41% n 147--15o 0., 0.32..-- Do.

OH: I 12 --do cH,cH,cmcH,--.'.-- cmcfloomcmm 153-160C.,0.25. Do.

(lJHa 13. .-do CH;CH; cmcmconm 14s-14e 0., .03..-- Do.

CHr-CH: 14 do cmcmcoN CH: -162C.,0.05- Do.

CHI-C I Clix-C is n n cmcncoN cH=- 152-155C.,0.015 Do.

, cHcfi1 CHI-CHI m n cm H.CON o 15o= 151 0., 0.02.--- Do.

CHPC: I 11 do CH:CH| cmcmcommnm 191-2ooc.o.o4.-- Viscous.

I 1s '..--do.--..- cH cH= CH:CH.CONH.C,H -1730.,0.4.--.- Liquid.

19 -cm -110 cnlcmomcmcomcnm 127-1'29C.,0.02.. Do.

20 n .....d cn cmcmcmcmcomcm), 15s1600.,0.s.. Do.

21-.-.-. cmn cmcnlcmcacomcm 163-166 c.,o.55--.. Do.

22 cm -CH:.CH; cmcmcmcmcoN c,H. 131-133 0., 0.02-.-. Do.

23 "do CH1CHa CHzCHfiHgCHgECQN(G;H;);.; 14o-1430.,o.o2-. Do;

I 24 -C1H| -cm cmcmcmcmcmcomcmn s1-1a9c.,o.os. Do. 25 do -cH,cF us -149 0., one-.- Do.

26........--..do CH: cmcmcmcmcomcim 13s=-1a9c.,o.os.;-. Do.

Table 2-Contlnued No. Ru=Ra Rn R B. P., mm. Form 21 421m -01H. omcmcmmoomcmm 141-143o.,o.oa..-. Liquid 2s --do cmcmomommcommm 1as-141o.,o.o2 Do.

CE: 29 n do CH( 7H.CON(C;H;)g 1a4-1a7o.,o.o2.... Do.

EXAMPLE 3 The compounds mentioned in the Examples 2 55.8 parts of a-ethyl amino butyric acid diethyl amide (made from a-bromobutyric acid diethyl amide and ethyl amine) are dissolved in 150 parts of tetraline, then under stirring at 180- 190 C. 31.2 parts of a-blOIIlODIOIJiOHiC acid diethyl amide are caused to drop thereinto, whereupon the mixture is maintained for 12 hours at this temperature. as described in Example 1. The N-ethyl-iminobutyric acid propionic acid bis-diethyl amide boils at a pressure of 0.2 mm. at 145-l47 C. It

The working up takes place= forms with acids easily soluble, neutral salts.

In the following Table 3 further compounds of the general formula CHaCHfllJELCON and 3 and in the tables belonging thereto can be produced, as has been described in Example 1, according to both the cited methods.

EXAMPLE 4 149.5 parts of chloracetic acid diethyl amide are dissolved in 200 parts of benzene and heated for 3 hours in the autoclave to 120 C. with 90 parts of ethyl amine. The ethyl amine hydrochloride thus formed is filtered by suction, the benzene solution washed with caustic potash lye, freed from the solvent and distilled.

The first running consists of ethyl amino acetic 'acid diethyl amide; boiling point at 20 mm. pressure=1l3-115 C. The N-ethyl-imino-dieacetic acid bis-diethyl amide distills at 0.4 mm. pressure 30 at 158-159 C. and constitutes a colorless liquid Ro R2 being easily soluble in water and organic solvents and producing neutral salts by means of acids. are enumerated. The N-ethyl-imino-di-acetic acid bis-diethyl Table 3 N0. R1 R1 R0 I R B. P., mm. Form l 1 CH; -CH; -CHCH3 CHZCH-CON(CHS)(C3H7) 142145C.,0.45 Liquid.

2 d0 do CHzCHzCH2CHz CHaJJH-CON(CH:):--; 127130 0., 0.04.-.. Do.

I a do do OH; CHsOH.CON(CzHs)z 142-145 0., 0.21m- D0.

4 "do do -cm l32 0., c.1s. Do.

5 c,H, -o,11, CHa CHaEECONwHm 139-140 0.,o.2- Do.

a do do CH2CH= CH3H-C N( H3)(C1H7) 144-1460.,0.25 D0.

7. CH; -410 CH3 CHa J C N(CzHa): 129-132 0., 0.02---- Do.

a do do -CHzCH1 ----.do 130l33 0., 0.05---- Do,

9 C1H5 do -CHzCH2CzCHa-. CHaH-CDNKCHD: 141144C.,0.1 Do

10 do do -0H3-. CH3CH-CQN(CIH5)1 14a-14co..o.15 Do.

11 do do -CHzCHzCHCH3 do -14s 0., 0.18..-. Do.

I 12---- -cm CH3 -CH2CH 1. cHacHzcHcoNgcmn 115-117C.,o.03 Do.

, I 13 do do C}I3 CH3CH2CH-CON(C2H)2 1ss-1410.,o.25... Do.

14---- -dn do CH2CFI- do 123126" 0., 0.02." Do.

i ,m -c7m do 1a5-1a70.,0.03.... Do.

CH: 16 CH3 -CH: 43g CHaH-C0N(C2Hs)z 125-128 C.,0.03 D0.

/CHr-CH: CH; 17.... -C 152-155 0., o.o2 Do.

CHz-Cfiz 18.-.- --CH CH=CEg -CH;OH=CH-. 14s-151 0., 0.03-"- Do.

I 19 c,m -c-m oniomcmcficooczmnuu 121-124 0., 0.03..-- Do.

20.... -cm R -0H=00N(C2H.)= -188C.,0.6. Do.

9 amide may also be prepared more advantageously according to the method described in Example 1.

From the ethyl amino acetic diethyl amide obtainable as by-product it is possible to produce compounds according to the present invention when working in accordance with the methods of the Examples 1 to 3 by interaction with chloracetic acid and by neutralisation with chloracetic ester, chloraceto-nitrile, etc.

EXAMPLE 5 36 parts of a-N-ethyl-imino-butyric acid ethyl amide acetic acid diethyl amide (see table Example 1) having the formula are dissolved in .x'ylene, treated with 4 parts of sodium amide and heated for some time on the water-bath until no more ammonia is developed. Then the sodium compound is heated in the autoclave at 180-190 C. with 16.5 parts of potassium ethyl sulfate. After having separated the potassium sodium sulfate the solvent is distilled oil and the N-ethyl-imino-butyric acid acetic acid bis-diethyl amide is rectified in the high-vacuo. B. P.o.o3 mm. 134-1 '36 C.

The same compound can also be prepared according to anyone of the methods described in the above process.

Exim-Ls 6 27.1"paits of a-imino-dipropionic acid bis-di-' ethyl amide oi the formula are heated for several hours on the water-bath with 13.5 parts of 85% formic acid and 20 parts of 35% formaldehyde. Then 12 parts of concentrated hydrochloric acid are added thereto. and the formic acid as well as the excess of formaldehyde are distilled oil. The residue is treated with water and saturated with potassium hydroxide. The formed N-methyl-imino-di-(propionic acid 'diethylamide) is dissolved in benzene and dried over solid potassium hydroxide.- After distillation of the solvent it is rectified in high-vacuo. B. P.o.c1 mm. 133 C.

The same compound may also be produced ac cording to the method described in Example 2. By methylation with dimethyl sulfate or methyl iodide the same compound is obtained, while analogous derivatives may be prepared by interaction with other alkylating agents or also with aralkylating agents like diethyl sulfate,- ethyl chloride, benzyl chloride, phenyl ethyl bromide and so on.

EXAMPLE 7 30 parts of a-N-ethyl-imino-di-n-butyric acid diethyl ester of the formula omomomoooom.

HCLN cmcmdmooocm.

(made from a-bromobutyric acid ethyl ester and ethyl amine) are boiled under reflux for several hours with concentrated hydrochloric acid. Then the solution is concentrated by evaporation to dryness and heated for some time to 50 C. with the calculated quantity of phosphorus pentachloride. After having eliminated the phosphorus oxychloride in vacuo one obtains the hydrochloride of the N-ethyl-imino-di-n-butyric acid dichloride which is introduced into an excess of a diethyl amine solution, After having removed the diethyl amine hydrochloride by filtration, there is distilled in the high-vacuo. Thus the N-ethyl-imino-di-n-butyric acid bis-diethyl amide wherein R5 and R6 each represents a member selected from the group consisting of H and lower alkyl, R0 represents a member selected from the group consisting of lower alkyl, allyl, benzyl, phenethyl and cyclohexyl, R1 represents a member selected from the group consisting of H, lower alkyl and allyl, and R2, R3 and R4 each represents a member selected from the group consisting of lower alkyl and ally].

2. An imino-di-fatty acid amide of the formula wherein R5 and Rs each represents a member selected from the group consisting of H and lower alkyl, and R0 represents a member selected from the group consisting of lower alkyl, allyl, benz'yl, phenethyl and cyclohexyl.

3. An imino-di-fatty acid amide of the formula Y wherein R5 and R6 each represents a member selected from th group consisting of H and lower alkyl, and R0 represents a member selected from the group consisting of lower alkyl, allyl, benzyl, phenethyl and cyclohexyl.

4. An imino-di-fatty acid amide of the formula R;(|JH.'C0.N(C1H;)| Re-N RPH.CO.N(CHI)2 wherein R5 and Rs each represents a member selected from the group consisting of H and lower alkyl, and R0 represents a member selected from the group consisting of lower alkyl, allyl, benzyl, phenethyl and cyclohexyl.

5. An imino-di-fatty acid amide of the .formula wherein R represents a member selected from the group consisting of lower alkyl, allyl, benzyl, phenethyl and cyclohexyl, R1 represents a member selected from the group consisting of H, lower wherein R5 and Rs each represents a member selected from the group consisting of H and lower alkyl, R1 represents a member selected from the group consisting of H, lower alkyl, and allyl and R2, R3 and R4 each represents a member selected from the group consisting of lower alkyl and allyl.

7. The imino-di-fatty acid amide of the following formula cm-oncomcm' CH;(CH2)aN Y CHr- 11.0 0.N(CH3)Z being a colorless liquid of the boilin point at 0.09 mm. pressure of 132-l35 C.

8. The imino-di-fatty acid amide of the following formula being a colorless liquid of the boiling point at 0.09 mm. pressure of 133-136 C.

9. The imino-di-fatty acid amide of the following formula 7 being a colorless liquid of the boiling point at 0.12

mm. pressure of 148-151 C,

HENRY MARTIN. HANS GYSIN; 

